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Journal of Traditional Chinese Medicine logoLink to Journal of Traditional Chinese Medicine
. 2025 Sep 15;45(5):963–969. doi: 10.19852/j.cnki.jtcm.2025.05.003

Shisiwei Jianzhong decoction (十四味建中汤) inhibits the adipogenic differentiation of bone marrow mesenchymal stem cells by downregulating nuclear factor of activated T cells, cytoplasmic 4 in non-severe aplastic anemia

Jun WANG 1, Bo WANG 1, Yun ZHANG 1, Shengyun LIN 1, Liqiang WU 1,✉
PMCID: PMC12453986  PMID: 41015794

Abstract

OBJECTIVE:

To investigate the effect of Shisiwei Jianzhong decoction (十四味建中汤, SJD) on non-severe aplastic anemia (NSAA).

METHODS:

Bone marrow mesenchymal stem cells (BMSCs) were isolated from bone marrow samples of 15 NSAA patients and 3 healthy controls. Cells were treated with gradient concentrations of SJD, and a portion was transfected with a vector overexpressing the nuclear factor of activated T cells, cytoplasmic 4 (NFATC4). Cell viability and apoptosis were detected by cell counting kit-8 and flow cytometry, respectively. After adipogenic differentiation induction, lipid droplet formation in BMSCs was examined by Oil Red O staining. The expression of NFATC4, peroxisome proliferator-activated receptor gamma (PPARG), fatty acid-binding protein 4 (FABP4), peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), and acetylated PGC-1α was measured by quantitative real-time polymerase chain reaction or Western blot.

RESULTS:

SJD significantly increased the viability and decreased the apoptosis of NSAA-derived BMSCs. It also dose-dependently inhibited lipid droplet formation and decreased the expression of PPARG and FABP4 in NSAA-derived BMSCs. NFATC4 expression was higher in patients with NSAA than in healthy controls, and SJD downregulated its expression. NFATC4 overexpression reversed the inhibitory effect of SJD on adipogenic differentiation. Additionally, SJD promoted the deacetylation of PGC-1α in NSAA-derived BMSCs, which was also partially eliminated by NFATC4 overexpression.

CONCLUSIONS:

SJD inhibits adipogenic differentiation of BMSCs through downregulating NFATC4, thereby contributing to the remission of NSAA.

Keywords: NFATC transcription factors, aplastic anemia, adipogenic differentiation, bone marrow stem cells, Shisiwei Jianzhong decoction

1. INTRODUCTION

Aplastic anemia (AA) is a bone marrow failure syndrome characterized by pancytopenia in the bone marrow and peripheral blood.1 AA is classified into non-severe AA (NSAA), severe AA (SAA), and very severe AA, with NSAA comprising approximately 80% of cases.2,3 Although NSAA is not immediately life-threatening, it may progress without treatment.4 Hematopoietic stem cell transplantation and immunosuppressive therapy are effective treatments for AA but are constrained by factors such as patient age, donor matching, and low response.3 In China, cyclosporine A (CsA) is commonly used to treat NSAA, but managing its concentration is challenging due to its toxicity.5 This emphasizes the need for more effective and safer therapeutic options for NSAA.

Traditional Chinese Medicine (TCM) has shown significant advantages in treating various diseases, including AA.6-8 Shisiwei Jianzhong decoction (十四味建中汤, SJD), a traditional herbal formula, consists of 14 herbs: Rougui (Cortex Cinnamomi Cassiae), Fuzi (Radix Aconiti Lateralis Preparata), Huangqi (Radix Astragali Mongolici), Danggui (Radix Angelicae Sinensis), Chuanxiong (Rhizoma Chuanxiong), Dihuang (Radix Rehmanniae), Baishao (Radix Paeoniae Alba), Dangshen (Radix Codonopsis), Baizhu (Rhizoma Atractylodis Macrocephalae), Fuling (Poria), Maidong (Radix Ophiopogonis Japonici), Mudanpi (Cortex Moutan Radicis), Roucongrong (Herba Cistanches Deserticolae), and Gancao (Radix Glycyrrhizae). SJD functions to warm Yang, nourish the kidneys, and invigorate the spleen. Previous research has revealed the therapeutic potential of SJD in AA.9 Notably, Huangqi (Astragalus Membranaceus) and Danggui (Angelica Sinensis) are extensively used in treating anemia.9 Ginsenoside Rg1 restores hematopoietic function in AA by suppressing mitochondrial apoptosis in bone marrow mononuclear cells.10 Danggui (Angelica Sinensis) polysaccharide restores the function of hematopoietic stem cells by inhibiting abnormal T-cell immunity.11 Dihuang (Radix Rehmanniae) polysaccharide regulates the bone marrow microenvironment in AA.12 However, the effect of SJD on NSAA remains unclear.

Bone marrow mesenchymal stem cells (BMSCs) are essential to the hematopoietic niche.13 Increased adipogenic differentiation of BMSCs impairs hematopoietic function, promoting AA progression.14 Certain genes, such as ten-eleven-translocation 215 and DNA methyltransferase 1,16 can regulate adipogenic differentiation of BMSCs to alleviate AA. The nuclear factor of activated T cells, cytoplasmic 4 (NFATC4), a DNA-binding transcription complex, plays an important role in immune responses and influences multiple cellular processes, including cell development, differentiation, and apoptosis.17,18 Research has reported that all-trans retinoic acid ameliorates immune-mediated AA by targeting NFAT1 signaling, thereby influencing T-cell differentiation.19 However, the specific regulatory role of NFATC4 in BMSCs differentiation in AA remains unexplored. Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) is a transcriptional coactivator involved in energy metabolism, mitochondrial biogenesis, and oxidative stress responses. Its deficiency in maturing erythroid cells leads to severe anemia.20 Moreover, NFATC4 exacerbates mitochondrial dysfunction by promoting PGC-1α acetylation. Therefore, we speculate that NFATC4 may improve NSAA by regulating PGC-1α acetylation.

This study evaluated the therapeutic potential of SJD in NSAA in BMSCs. As our previous network pharmacology study identified NFATC4 as an active target of SJD in NSAA (unpublished), we further analyzed the underlying mechanism of SJD involving NFATC4.

2. MATERIALS AND METHODS

2.1. Isolation, culturing, and identification of BMSCs

BMSCs were isolated from bone marrow samples of 15 patients with NSAA and 6 healthy controls. Briefly, diluted whole blood was added to separation solution and centrifuged at 1000 × g for 20-30 min. Cells in the buffy coat were collected, washed with PBS, and resuspended in PBS. Centrifugation at 250 × g for 10 min was repeated twice to obtain bone marrow samples. The isolated cells were resuspended in Dulbecco's Modified Eagle Medium containing 10% fetal bovine serum and cultured at 37 ℃ with 5% CO2. Third-generation BMSCs were used for identification, the morphology of BMSCs was observed under a microscope (CKX53, Olympus, Tokyo, Japan), and the surface markers [CD29, CD44, CD105, CD34, CD45, and human leukocyte antigen-DR isotype (HLA-DR)] were detected by flow cytometry (CytoFLEXS, Beckman, Miami, FL, USA). This study was approved by the Ethics Committee of the local Hospital in accordance with the Declaration of Helsinki (approval number: 2020-KL-054-01). Written informed consent was obtained from all participants.

2.2. SJD preparation

SJD was obtained from the pharmacy of the First Affiliated Hospital of Zhejiang Chinese Medical University (Hangzhou, China). After the SJD decoction was concentrated for 1 h, the residue was filtered out, yielding approximately 100 mL of liquid. The liquid was centrifuged at 14 000 rpm, and the supernatant was collected. The supernatant was then passed through a 100-mesh filter and lyophilized for 72 h.

2.3. Treatment and transfection of BMSCs

BMSCs from NSAA patients were treated with gradient concentrations of SJD (0.08, 0.8, 8, and 80 µg/mL) for 48 h. Overexpression vector pCDNA3.1 carrying NFATC4 (oe-NFATC4) and empty vector (oe-NC) were packaged in lentivirus (GenePharma, Shanghai, China). BMSCs were transfected with oe-NFATC4/oe-NC using Highgene transfection reagent (ABclonal, Wuhan, China) for 48 h and then treated with 80 µg/mL of SJD for another 48 h. BMSCs treated with CsA (1 μM, Cayman Chemical, Ann Arbor, MI, USA) for 24 h served as a positive control. BMSCs without treatment and/or transfection were used as the control group.

2.4. Cell viability assay

Cell viability was detected using cell counting kit-8 (CCK-8, Beyotime, Beijing, China) according to the manufacturer's instructions. Absorbance was measured at 450 nm by a microplate reader (DR-3518G, Hiwell Diatek, Wuxi, China).

2.5. Cell apoptosis assay

Apoptosis was detected by flow cytometry (CytoFLEXS, Beckman, CA, USA) using an Apoptosis Detection Kit (Beyotime, Beijing, China) according to the manufacturer's instructions.

2.6. Oil red O staining

BMSCs were alternately incubated in ADP1 medium (Procell, Wuhan, China) for 3 d and in ADP2 medium (Procell, Wuhan, China) for 1 d. After 14 d of differentiation, cells were fixed with 4% paraformaldehyde for 10 min and then stained with Oil Red O (Beyotime, Beijing, China) for 15 min. Lipid droplet formation was observed under a microscope (Olympus, Tokyo, Japan).

2.7. Quantitative real-time polymerase chain reaction (qRT-PCR)

Total RNA in BMSCs was extracted using TRIzol (Invitrogen, Carlsbad, CA, USA). cDNA was reverse-transcribed from RNAs using First-strand cDNA Synthesis Mix (Tiangen, Beijing, China). PCR thermal cycling conditions were 95 ℃ for 3 min followed by 40 cycles of 95 ℃ for 12 s and 62 ℃ for 40 s. Relative mRNA expression of target genes was calculated by the 2-∆∆Ct method, with β-actin as an internal control. The primers used were: NFATC4-F: 5′-ACC CTA CAG ATG TTC ATC GGC-3′, NFATC4-R: 5′-ATT CCC GCG CAG TCA ATG T-3′; PPARG-F: 5′-CTC CTA TTG ACC CAG AAA GC-3′, PPARG-R: 5′-GTA GAG CTG AGT CTT CTC AG-3′; FABP4-F: 5′-GTC CAG GCT GGA ATG CAG TG-3′, FABP4-R: 5′-CAC ACA GAC GTA CAG AGT GG-3′; β-actin-F: 5′-CCA TCG TCC ACC GCA AAT-3′, β-actin-R: 5′-GCT GTC ACC TTC ACC GTT CC-3′.

2.8. Western blot

Total proteins from BMSCs were extracted using radio-immunoprecipitation assay buffer (Beyotime, Beijing, China). Protein samples were separated by electrophoresis and transferred to PVDF membranes. After blocking with 5% nonfat milk for 1 h, the membrane was incubated with primary antibodies at 4 ℃ overnight (1∶2000, Abcam, Cambridge, UK), including anti-NFATC4, -peroxisome proliferator-activated receptor gamma (PPARG), -fatty acid-binding protein 4 (FABP4), -PGC-1α, -Ac-PGC-1α, and -glyceraldehyde-3-phosphate dehydrogenase. The membrane was incubated with secondary goat anti-rabbit IgG antibody (1∶2000, Abcam, Cambridge, UK) for 1 h at 25 ℃. The blots were visualized using chemiluminescence reagent (Pierce, Rockford, IL, USA).

2.9. Statistical analysis

Experiments were performed at least in triplicate. Results are exhibited as mean ± standard deviation and were analyzed using GraphPad Prism 7.0 (GraphPad, San Diego, CA, USA). Comparisons between two or multiple groups were made using t-test and one-way analysis of variance, with P < 0.05 regarded as significantly different.

3. RESULTS

3.1. SJD inhibited apoptosis of BMSCs

BMSCs isolated from both NSAA patients and healthy controls presented typical morphology of spindle (supplementary Figure 1A). Flow cytometry determined that the isolated BMSCs were positive for CD29, CD44, and CD105, but negative for CD34, CD45, and HLA-DR (supplementary Figure 1B).

Compared to the controls, the NSAA group exhibited decreased cell proliferation, increased cell apoptosis, and enhanced adipogenic differentiation (supplementary Figures 2A-2C).

NSAA-derived BMSCs were treated with SJD. SJD significantly increased the viability of BMSCs at a concentration of 80 µg/mL (P < 0.01, Figure 1A). Additionally, SJD significantly decreased the apoptosis of BMSCs in a dose-dependent manner (P < 0.05, Figure 1B).

Figure 1. SJD inhibited apoptosis of NSAA-derived BMSCs.

Figure 1

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A: cell viability was measured by CCK-8 assay; n = 4; B: cell apoptosis was measured by flow cytometry. B1: control group; B2: 0.08 μg/mL group; B3: 0.8 μg/mL group; B4: 8 μg/mL group; B5: 80 μg/mL group; B6: quantitative analysis of apoptosis. Control group: basal medium; 0.08 μg/mL group: BMSCs were treated with 0.08 μg/mL SJD for 48 h; 0.8 μg/mL group: BMSCs were treated with 0.8 μg/mL SJD for 48 h; 8 μg/mL group: BMSCs were treated with 8 μg/mL SJD for 48 h; 80 μg/mL group: BMSCs were treated with 80 μg/mL SJD for 48 h;. SJD: Shisiwei Jianzhong decoction; NSAA: non-severe aplastic anemia; BMSCs: bone marrow mesenchymal stem cells; CCK-8: cell-counting kit-8. Statistical analysis was performed using one-way analysis of variance. Data are exhibited as mean ± standard deviation (n = 3). Compared with Control group, aP < 0.01 and bP < 0.05.

3.2. SJD inhibited adipogenic differentiation of BMSCs

SJD inhibited lipid droplet formation with increasing doses (Figure 2A). The mRNA and protein expression of lipogenic markers PPARG and FABP4 were significantly decreased after SJD treatment in a dose-dependent manner (P < 0.05, Figures 2B, 2C).

Figure 2. SJD inhibited adipogenic differentiation of NSAA-derived BMSCs.

Figure 2

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A: oil Red O staining of lipid droplets (× 40, Scale bar = 50 µm). A1: Control group; A2: 0.08 μg/mL group; A3: 0.8 μg/mL group; A4: 8 μg/mL group; A5: 80 μg/mL group. Control group: basal medium; 0.08 μg/mL group: BMSCs were treated with 0.08 μg/mL SJD for 48 h; 0.8 μg/mL group: BMSCs were treated with 0.8 μg/mL SJD for 48 h; 8 μg/mL group: BMSCs were treated with 8 μg/mL SJD for 48 h; 80 μg/mL group: BMSCs were treated with 80 μg/mL SJD for 48 h; B: relative mRNA levels of PPARG and FABP4 were detected by qRT-PCR. B1: quantitative analysis of PPARG levels; B2: quantitative analysis of FABP4 levels; C: the protein levels of PPARG and FABP4 were detected by Western blot. C1: protein images of PPARG and FABP4; C2: quantitative analysis of PPARG levels; C3: quantitative analysis of FABP4 levels. SJD: Shisiwei Jianzhong decoction; NSAA: non-severe aplastic anemia; BMSCs: bone marrow mesenchymal stem cells; PPARG: peroxisome proliferator-activated receptor gamma; FABP4: fatty acid-binding protein 4; qRT-PCR: quantitative real-time polymerase chain reaction. Statistical analysis was performed using one-way analysis of variance. Data are exhibited as mean ± standard deviation (n = 3). Compared with Control group, aP < 0.05 and bP < 0.01.

3.3. SJD downregulated NFATC4 in BMSCs

The underlying mechanism of SJD involving NFATC4 was further explored. The mRNA and protein levels of NFATC4 were significantly higher in NSAA-derived BMSCs compared to controls (P < 0.01, Figure 3A). SJD significantly decreased NFATC4 expression at both the mRNA and protein levels, particularly at 80 µg/mL (P < 0.01, Figure 3B).

Figure 3. SJD downregulated NFATC4 in NSAA-derived BMSCs.

Figure 3

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A: mRNA and protein expression of NFATC4 in BMSCs from NSAA patients and healthy controls. A1: quantitative analysis of NFATC4 mRNA levels; A2: protein images of NFATC4; A3: quantitative analysis of NFATC4 protein levels. Healthy control group: BMSCs isolated from healthy controls; NSAA group: BMSCs isolated from patients with NSAA; n = 6; statistical analysis was performed using t-test; B: mRNA and protein expression of NFATC4 in SJD-treated BMSCs from NSAA patients. B1: quantitative analysis of NFATC4 mRNA levels; B2: protein images of NFATC4; B3: quantitative analysis of NFATC4 protein levels. Control group: basal medium; 0.08 μg/mL group: BMSCs were treated with 0.08 μg/mL SJD for 48 h; 0.8 μg/mL group: BMSCs were treated with 0.8 μg/mL SJD for 48 h; 8 μg/mL group: BMSCs were treated with 8 μg/mL SJD for 48 h; 80 μg/mL group: BMSCs were treated with 80 μg/mL SJD for 48 h. SJD: Shisiwei Jianzhong decoction; NFATC4: nuclear factor of activated T cells, cytoplasmic 4; NSAA: non-severe aplastic anemia; BMSCs: bone marrow mesenchymal stem cells. Statistical analysis was performed using one-way analysis of variance. Data are exhibited as mean ± standard deviation (n = 3). Compared with Healthy control (A) or Control (B), aP < 0.01 and bP < 0.05.

3.4. NFATC4 reversed the inhibitory effects of SJD on adipogenic differentiation and Ac-PGC-1α expression in BMSCs

NFATC4 was overexpressed in BMSCs to further confirm the underlying mechanism of SJD involving NFATC4. Transfection with oe-NFATC4 significantly upregulated both the mRNA and protein levels of NFATC4 in BMSCs (P < 0.01, Figures 4A, 4B). Overexpression of NFATC4 weakened the inhibitory effects of SJD on adipogenic differentiation of BMSCs (Figure 4C). Moreover, SJD significantly upregulated PGC-1α and downregulated Ac-PGC-1α in BMSCs (P < 0.05). The promoting effect of SJD on PGC-1α deacetylation was partially eliminated by NFATC4 overexpression (P < 0.01, Figure 4B).

Figure 4. NFATC4 overexpression reversed the effects of SJD on adipogenic differentiation and PGC-1α acetylation in NSAA-derived BMSCs.

Figure 4

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A: relative mRNA expression of NFATC4 in SJD-treated BMSCs was detected by qRT-PCR. Control group: basal medium; CsA group: CsA (1 μM); SJD group: SJD (80 µg/mL); SJD + oe-NC group: SJD (80 µg/mL) treated with oe-NC BMSCs; SJD + oe-NFATC4 group: SJD (80 µg/mL) treated with oe-NFATC4 BMSCs; B: protein levels of NFATC4, PGC-1α, and Ac-PGC-1α in SJD-treated BMSCs were detected by Western blot. B1: protein images of NFATC4, PGC-1α, and Ac-PGC-1α; B2: quantitative analysis of NFATC4 protein levels; B3: quantitative analysis of PGC-1α protein levels; B4: quantitative analysis of Ac-PGC-1α protein levels. C: oil red O staining of lipid droplets (× 40, Scale bar = 50 µm). C1: Control group; C2: CsA group; C3: SJD group; C4: SJD + oe-NC group; C5: SJD + oe-NFATC4 group. NFATC4: nuclear factor of activated T cells, cytoplasmic 4; SJD: Shisiwei Jianzhong decoction; PGC-1α: peroxisome proliferator-activated receptor-gamma coactivator; NSAA: non-severe aplastic anemia; BMSCs: bone marrow mesenchymal stem cells; qRT-PCR: quantitative real-time polymerase chain reaction; CsA: cyclosporine A. Statistical analysis was performed using one-way analysis of variance. Data are exhibited as mean ± standard deviation (n = 3). Compared with control group, aP < 0.01 and cP < 0.05; compared with SJD + oe-NC group, bP < 0.01.

4. DISCUSSION

NSAA is a mild form of AA characterized by hypocellular marrow and peripheral blood cytopenia.4 Current treatments, such as CsA, are limited due to low response, side effects, and relapses.21 Adipogenic differentiation of BMSCs can inhibit the hematopoietic function of bone marrow, and its inhibition has become a potential therapy for NSAA.13 This study investigated the therapeutic potential of SJD in NSAA and found that SJD enhanced the viability and inhibited adipogenic differentiation of NSAA-derived BMSCs through the NFATC4/PGC-1α axis.

TCM is widely used for treating various diseases.22 SJD, a compound TCM, has been commonly applied in hematopoietic disease treatment, particularly anemia.23 Our results revealed that SJD increased the viability and decreased the apoptosis of NSAA-derived BMSCs. Notably, SJD weakened adipogenic differentiation of NSAA-derived BMSCs, as evidenced by decreased lipid droplets and downregulation of the lipogenic markers. Enhanced adipogenic differentiation of BMSCs is a key pathogenic driver of AA; hence, SJD may relieve NSAA by inhibiting adipogenic differentiation of BMSCs.

Several genes, such as BMP4,24 FAM13A,25 and ZFP36L1,26 are involved in adipogenic differentiation of BMSCs in AA, with some also linked to the mechanisms of specific drugs. This study selected NFATC4 as a potential target to explore the mechanisms of SJD in NSAA. Results showed that SJD downregulated NFATC4 expression in NSAA-derived BMSCs. NFATC4 is a member of the NFATC family, originally identified in T-cells.27 Except for its role in immune system, NFATC also regulates osteogenic differentiation of BMSCs. Saidak et al 28 found that strontium ranelate inhibits the differentiation of BMSCs from osteoblasts to adipocytes in senescent osteopenic mice by regulating the NFATC/Maf signaling. Huh et al 29 reported that arginine promotes osteoblastogenesis and suppresses adipogenesis of BMSCs through NFATC signaling. Our results revealed that NFATC4 overexpression reversed the inhibitory effects of SJD on adipogenic differentiation, suggesting that SJD may inhibit the adipogenic differentiation of NSAA-derived BMSCs by downregulating NFATC4 expression. Moreover, NFAT signaling also inhibits myeloid hematopoiesis.30 Thus, the downregulation of NFATC4 induced by SJD may also benefit the treatment of NSAA through hematopoiesis improvement.

PGC-1α, a master regulator of mitochondrial biogenesis, is activated through phosphorylation or deacetylation.31,32 It is highly expressed in maturing erythroid cells, and its deficiency leads to growth retardation and profound anemia in neonatal mice.20 Moreover, the regulatory role of PGC-1α in adipogenic differentiation has been increasingly acknowledged. Yu et al 33 found that loss of PGC-1α promotes adipogenic differentiation of murine skeletal stem cells at the expense of osteoblastic differentiation. Li et al 34 showed that celastrol enhances osteoblast differentiation and inhibits adipogenic differentiation of BMSCs by activating PGC-1α. In this study, SJD significantly upregulated PGC-1α and downregulated Ac-PGC-1α in BMSCs, indicating that the inhibitory effect of SJD on adipogenic differentiation is associated with PGC-1α activation. Previous research also determined that NFATC4 enhances phenylephrine-induced mitochondrial dysfunction by promoting PGC-1α acetylation.35 Consistently, NFATC4 overexpression increased AC-PGC-1α expression in SJD-treated BMSCs. Therefore, SJD may inhibit the adipogenic differentiation of NSAA-derived BMSCs by regulating NFATC4-mediated PGC-1α activation.

In conclusion, SJD enhanced the viability and inhibited adipogenic differentiation of NSAA-derived BMSCs through downregulation of NFATC4 and its mediated PGC-1α activation, contributing to NSAA remission. These findings reveal that SJD is a potential drug for NSAA. However, this study was limited to the cellular level, necessitating clinical validation in NSAA patients. Further research is required to identify and characterize active components of SJD, crucial for understanding and optimizing its therapeutic efficacy.

5. SUPPORTING INFORMATION

Supporting data to this article can be found online at http://www.journaltcm.com.

JTCM-43-5-963-s1.pdf (689.8KB, pdf)

Funding Statement

Supported by Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project: Research on the Mechanism of Shisiwei Jianzhong Decoction in Treating Non-severe Aplastic Anemia with Kidney Yang Deficiency Based on the C Vactivated T Nuclear Factor (NFATc4) (2020ZB086) and Zhejiang Province Traditional Chinese Medicine Science and Technology Youth Talent Plan Project: Study on the Academic thought and Clinical Application of Professor Zhou Yuhong in the Treatment of Chronic Aplastic Anemia (2021ZQ029)

REFERENCES

  • 1. Javan MR, Saki N, Moghimian-Boroujeni B. Aplastic anemia, cellular and molecular aspects. Cell Biol Int 2021; 45: 2395-402. [DOI] [PubMed] [Google Scholar]
  • 2. Liu H, Zheng X, Zhang C, et al. Outcomes of haploidentical bone marrow transplantation in patients with severe aplastic anemia-Ⅱ that progressed from non-severe acquired aplastic anemia. Front Med 2021; 15: 718-27. [DOI] [PubMed] [Google Scholar]
  • 3. Guan J, Zhao Y, Wang T, Fu R. Traditional Chinese Medicine for treating aplastic anemia. J Pharm Pharm Sci 2023; 26: 11863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Kwon JH, Kim I, Lee YG, et al. Clinical course of non-severe aplastic anemia in adults. Int J Hematol 2010; 91: 770-75. [DOI] [PubMed] [Google Scholar]
  • 5. Gao X, Bian ZL, Qiao XH, et al. Population pharmacokinetics of cyclosporine in Chinese pediatric patients with acquired aplastic anemia. Front Pharmacol 2022; 13: 933739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Yang CY, Luo J, Peng WJ, Dai WB. Huaiyu pill alleviates inflammatory bowel disease in mice blocking toll like receptor 4/ myeloid differentiation primary response gene 88/ nuclear factor kappa B subunit 1 pathway. J Tradit Chin Med 2024; 44: 916-25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Zhang L, Ni R, Li J, et al. Dioscin regulating bone marrow apoptosis in aplastic anemia. Drug Des Devel Ther 2022; 16: 3041-53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Jiang ZY, Yu FQ, Gao RL, et al. Treatment of chronic aplastic anemia with Chinese patent medicine Pai-Neng-Da capsule for replacing androgen partially: a clinical multi-center study. Chin J Integr Med 2022; 28: 20-7. [DOI] [PubMed] [Google Scholar]
  • 9. Baak JPA, Deng P, Li X, et al. The herbal decoction modified Danggui Buxue Tang attenuates immune-mediated bone marrow failure by regulating the differentiation of T lymphocytes in an immune-induced aplastic anemia mouse model. PLoS One 2017; 12: e0180417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Cao H, Wei W, Xu R, Cui X. Ginsenoside Rg1 can restore hematopoietic function by inhibiting Bax translocation-mediated mitochondrial apoptosis in aplastic anemia. Sci Rep 2021; 11: 12742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Chen Z, Cheng L, Zhang J, Cui X. Angelica sinensis polysaccharide prevents mitochondrial apoptosis by regulating the Treg/Th17 ratio in aplastic anemia. BMC Complement Med Ther 2020; 20: 192. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 12. Liu NA, Liu JQ, Liu Y, et al. Rehmannia glutinosa polysaccharide regulates bone marrow microenvironment via HIF-1α/NF-κB signaling pathway in aplastic anemia mice. Anais da Academia Brasileira de Ciências 2023; 95: e20220672. [DOI] [PubMed] [Google Scholar]
  • 13. Gonzaga VF, Wenceslau CV, Lisboa GS, Frare EO, Kerkis I. Mesenchymal stem cell benefits observed in bone marrow failure and acquired aplastic anemia. Stem Cells Int 2017; 2017: 1-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Wang HY, Ding TL, Xie Y, Xu XP, Yu L, Chen T. Osteogenic and adipogenic differentiation of bone marrow-derived mesenchymal stem cells in patients with aplastic anemia. Zhong Hua Nei Ke Za Zhi 2009; 48: 39-43. [PubMed] [Google Scholar]
  • 15. Li N, Liu L, Liu Y, Luo S, Song Y, Fang B. miR-144-3p suppresses osteogenic differentiation of BMSCs from patients with aplastic anemia through repression of TET2. Mol Ther Nucleic Acids 2020; 19: 619-26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Li H, Xu X, Wang D, et al. Hypermethylation-mediated downregulation of long non-coding RNA MEG 3 inhibits osteogenic differentiation of bone marrow mesenchymal stem cells and promotes pediatric aplastic anemia. Int Immunopharmacol 2021; 93: 107292. [DOI] [PubMed] [Google Scholar]
  • 17. Xu Y, Yang L, Yu S, et al. Spatiotemporal changes in NFATc4 expression of retinal ganglion cells after light-induced damage. J Mol Neurosci 2013; 53: 69-77. [DOI] [PubMed] [Google Scholar]
  • 18. Zhang Y, Chen D, Zhao L, et al. Nfatc4 deficiency attenuates ototoxicity by suppressing Tnf-mediated hair cell apoptosis in the mouse cochlea. Front Immunol 2019; 10: 1660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Tang D, Liu S, Sun H, et al. All-trans-retinoic acid shifts Th1 towards Th2 cell differentiation by targeting NFAT1 signalling to ameliorate immune-mediated aplastic anaemia. Br J Haematol 2020; 191: 906-19. [DOI] [PubMed] [Google Scholar]
  • 20. Cui S, Tanabe O, Lim KC, et al. PGC-1 coactivator activity is required for murine erythropoiesis. Mol Cell Biol 2014; 34: 1956-65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Du Y, Huang Y, Zhou W, et al. Effective tacrolimus treatment for patients with non-severe aplastic anemia that is refractory/intolerant to cyclosporine A: a retrospective study. Drug Des Devel Ther 2020; 14: 5711-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Xu Q, Bauer R, Hendry BM, et al. The quest for modernisation of Traditional Chinese Medicine. BMC Complement Altern Med 2013; 13: 132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Sun Y, Zhang J, Chen Y. Efficacy and safety of Jianzhong decoction in treating peptic ulcers: a Meta-analysis of 58 randomised controlled trials with 5192 patients. BMC Complement Altern Med 2017; 17: 215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Cheng HC, Liu SW, Li W, et al. Arsenic trioxide regulates adipogenic and osteogenic differentiation in bone marrow MSCs of aplastic anemia patients through BMP 4 gene. Acta Biochim Biophys Sin (Shanghai) 2015; 47: 673-9. [DOI] [PubMed] [Google Scholar]
  • 25. Wang E, Zhang Y, Ding R, Wang X, Zhang S, Li X. miR30a5p induces the adipogenic differentiation of bone marrow mesenchymal stem cells by targeting FAM13A/Wnt/betacatenin signaling in aplastic anemia. Mol Med Rep 2022; 25: 27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Liu LL, Liu L, Liu HH, et al. Levamisole suppresses adipogenesis of aplastic anaemia-derived bone marrow mesenchymal stem cells through ZFP36L1-PPARGC1B axis. J Cell Mol Med 2018; 22: 4496-506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Day CJ, Kim MS, Lopez CM, Nicholson GC, Morrison NA. NFAT expression in human osteoclasts. J Cell Biochem 2005; 95: 17-23. [DOI] [PubMed] [Google Scholar]
  • 28. Saidak Z, Haÿ E, Marty C, Barbara A, Marie PJ. Strontium ranelate rebalances bone marrow adipogenesis and osteoblastogenesis in senescent osteopenic mice through NFATc/Maf and Wnt signaling. Aging Cell 2012; 11: 467-74. [DOI] [PubMed] [Google Scholar]
  • 29. Huh JE, Choi JY, Shin YO, et al. Arginine enhances osteoblastogenesis and inhibits adipogenesis through the regulation of Wnt and NFATc signaling in human mesenchymal stem cells. Int J Mol Sci 2014; 15: 13010-29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Fric J, Lim CXF, Koh EG, et al. Calcineurin/NFAT signalling inhibits myeloid haematopoiesis. EMBO Mol Med 2012; 4: 269-82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res 2008; 79: 208-17. [DOI] [PubMed] [Google Scholar]
  • 32. Li PA, Hou X, Hao S. Mitochondrial biogenesis in neurodegeneration. J Neurosci Res 2017; 95: 2025-9. [DOI] [PubMed] [Google Scholar]
  • 33. Yu B, Huo L, Liu Y, et al. PGC-1α controls skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal aging by inducing TAZ. Cell Stem Cell 2018; 23: 615-23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Yu S, Han B, Bai X, et al. The cold-soaking extract of Chinese yam (dioscorea opposita Thunb.) protects against erectile dysfunction by ameliorating testicular function in hydrocortisone-induced KDS-Yang rats and in oxidatively damaged TM3 cells. J Ethnopharmacol 2020; 263: 113223. [DOI] [PubMed] [Google Scholar]
  • 35. Yuan J, Xing H, Li Y, et al. EPB 41 suppresses the Wnt/β-catenin signaling in non-small cell lung cancer by sponging ALDOC. Cancer Letters 2021; 499: 255-64. [DOI] [PubMed] [Google Scholar]

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